More than 95% patients suffering from chronic myelogenous leukemia were found to have chromosome translocation which results in the formation of BCR-ABL fusion protein and thereby the activity of high expression of ABL tyrosine kinase. Accordingly, chronic myelogenous leukemia becomes the therapeutic target of Imatinib. Since human chronic myelogenous leukemia K562 cell expresses Bcr-Abl protein, it is the conventional cell model for studying drugs directing to BCR-ABL.
In the prior art, for example, a recombinant interferon α-2a has been used for the treatment of chronic myelogenous leukemia. This drug exhibits a wide-spectrum in antivirus, anti-tumor and immune regulation function. Interferon binds with the cell-surface receptors, and thereby induces the generation of a variety of antivirus proteins in the cells to inhibit the growth of virus therein and also strengthen the immune functions, such as enhancing the phagocytosis ability of macrophage and the cell toxicity of lymphocytes toward the target cells, and strengthening the function of natural killer cells.
Recently, Gleevec, namely Imatinib, has been used as the first-line treatment for chronic granulocyte leukemia. However, drug resistance was found in some patients after administration. As reported in some new studies, the second generation of Gleevec may overcome the Gleevec resistance in patients. Gleevec binds with BCR-ABL and hence inhibits the activity of BCR-ABL. BCR-ABL is an enzyme that promotes the growth of the white blood cells. In most cases, mutation of BCR-ABL causes drug resistance, which changes the shape of the enzyme and thereby drugs are not allowed to bind with it. Neil P. Shah and coworkers isolated an imatinib mutant, namely BMS-354825, which exhibits lower selectivity to BCR-ABL enzyme. The experiments were conducted by using mice model with leukemia and the culture of cells from leukemia patient, and the results show that BMS-354825 is more effective than Imatinib. Also, BMS-354825 can overcome most of the Imatinib resistance without showing any significant toxicity. (About 15-20% of Imatinib resistance is originated from another type of mutation, and this new drug is ineffective in these cases). Currently, BMS-354825 has entered phase I clinical trial (Overriding Imatinib Resistance with a Novel ABL Kinase Inhibitor, Neil P. Shah, et al.).
Before the discovery of Imatinib, IFN-α, cytosine arabinoside and hereditary hemorrhagic telangiectasia (HHT) are used independently or in combination for the treatment of Philadelphia Chromosome (Ph) positive chronic myelogenous leukemia (CML). Even though these drugs have been widely used, there are still many unsatisfactory effects in using them.